Modern medicine has focused its attention on the possibility of delivering drugs in a controlled manner, particularly as soon as more attractive targets have emerged, and new molecular tools have become available. Targeted cancer therapy has become an innovative strategy, with new drugs being constantly discovered and applied in the treatment of various types of tumors, enabling precision and personalized medicine. A major challenge concerns the safe delivery of drugs (minimizing side-effects) and the potential exploitation of novel molecular tools such as miRNA, CRISPR-Cas9, aptamers, and extracellular vesicles (EVs).
These approaches complement and integrate the use of more classical methods, such as antibody-based therapies, well-established and clinically effective in the field of cancer treatment [1].
We would like to thank everyone who made the publication of this Special Issue possible: the authors, peer reviewers, and editorial team. Everyone’s work has made it possible to explore such a vast and varied field of research, ultimately providing a broad and up-to-date overview of the strategies for targeted cancer therapy including the mechanisms and optimization of Targeted Radionuclide Therapy, the identification of new therapeutic targets such as CD320, and the role of molecular regulation in improving treatment strategies. It also highlights key signaling pathways involved in cancer progression and the development of more effective CAR-T cell therapies, with the overall goal of enhancing anti-cancer efficacy and improving patient outcomes.
Together, these studies suggest innovative strategies advancing modern cancer therapy—from improving CAR-T cell manufacturing and optimizing radiotherapy effects to developing molecularly targeted, immune-modulating, and anti-metastatic approaches. They collectively reflect a shift toward personalized, mechanism-based oncology aimed at overcoming resistance and reducing systemic toxicity.
Yassin et al. reports that CAR-T cell therapy has revolutionized the treatment of refractory hematologic cancers but faces production challenges, particularly low viral transduction efficiency and T-cell variability [2]. The proposed strategy involves culturing T cells in serum-free Nutri-T medium and treating them for 24 h with low doses of BX795 and rosuvastatin [3,4]. This combination improves CAR-T transduction and functionality, offering a promising method to produce more effective cells for cancer immunotherapy.
Ferro-Flores et al. examined Targeted Radionuclide Therapy (TRT) using radiopharmaceuticals to selectively deliver radiation to tumor cells while minimizing damage to healthy tissues. Beyond direct radiation effects, TRT induces non-targeted effects—such as bystander and abscopal responses—that enhance its therapeutic potential [5]. It also modulates immune responses, boosting the efficacy of combination therapies. Despite success in cancers like prostate and neuroendocrine tumors, challenges like hypoxia and radioresistance persist [6]. Advances in theranostics, AI, and precision dosimetry are paving the way for more personalized and effective TRT approaches.
Tolymbekova et al. examined the CD320 receptor, responsible for vitamin B12 uptake, overexpressed in several cancers and representing a potential selective therapeutic target [7]. Current strategies include vitamin B12-drug conjugates, CD320-specific antibodies or nanobodies, and nanoparticles carrying cytotoxic agents [8,9,10]. CD320 may also serve as an early cancer biomarker, but further in vivo studies are needed to assess its therapeutic safety and efficacy.
Ahmetoglu et al. investigated the role of guanylate-binding proteins (GBP1–7), interferon-inducible GTPases that defend against intracellular pathogens [11]. In cancer, their roles are context-dependent—they can either promote malignancy by enhancing immune signaling and therapy resistance or suppress tumors by activating immune pathways and regulating cell proliferation. Understanding GBP regulation could open up new opportunities for prognostic use and targeted cancer therapies [12,13,14].
Farhadi et al. studied the adaptor protein p130Cas that interacts with Crk and CrkL, regulating cell adhesion, migration, and invasion—processes crucial in tumor progression and metastasis [15,16,17]. Dysregulation of this signaling axis is linked to cancer development and aggressiveness. Targeting the p130Cas–Crk/CrkL complex could therefore inhibit cancer cell dissemination and serve as a novel therapeutic approach [18].
The ultimate goal of this Special Issue was to provide further ideas for developing innovative strategies, promoting collaboration between different disciplines, and thus contributing to the development of new, more effective, and sustainable treatments.
Seven manuscripts were submitted for consideration for the Special Issue and finally five papers were accepted for publication.
Funding
This Work is partially supported by a grant from the University of L’Aquila (Italy), Department of Life, Health and Environmental Sciences, to F.G. and R.I.
Conflicts of Interest
The authors declare no conflicts of interest.
List of Contributions
- Yassin, A.A.; Bhattacharya, B.; Radinsky, O.; Hadad, U.; Kaufman, B.; Porgador, A. Enhancing the Efficacy of CAR-T Cell Production Using BX795 and Rosuvastatin in a Serum-Free Medium. Int. J. Mol. Sci. 2025, 26, 2988. https://doi.org/10.3390/ijms26072988. PMID: 40243610; PMCID: PMC11988885.
- Ferro-Flores, G.; Azorín-Vega, E.; Ocampo-García, B.; Luna-Gutiérrez, M.; Cruz-Nova, P.; Meléndez-Alafort, L. Effects of Targeted Radionuclide Therapy on Cancer Cells Beyond the Ablative Radiation Dose. Int. J. Mol. Sci. 2025, 26, 6968. https://doi.org/10.3390/ijms26146968. PMID: 40725216; PMCID: PMC12296037.
- Tolymbekova, A.; Lezina, L. CD320 Receptor and Vitamin B12 as Potential Targets for Anti-Cancer Therapy. Int. J. Mol. Sci. 2025, 26, 5652. https://doi.org/10.3390/ijms26125652. PMID: 40565117; PMCID: PMC12193483.
- Ahmetoglu, D.; Zheng, H.; Swart, A.; Zhu, H.; Li, M. Multifaceted Roles of Guanylate-Binding Proteins in Cancer. Int. J. Mol. Sci. 2025, 26, 5477. https://doi.org/10.3390/ijms26125477. PMID: 40564939; PMCID: PMC12193362.
- Farhadi, P.; Park, T. The p130Cas-Crk/CrkL Axis: A Therapeutic Target for Invasive Cancers Unveiled by Collaboration Among p130Cas, Crk, and CrkL. Int. J. Mol. Sci. 2025, 26, 4017. https://doi.org/10.3390/ijms26094017. PMID: 40362257; PMCID: PMC12071665.
References
- Kothari, M.; Wanjari, A.; Acharya, S.; Karwa, V.; Chavhan, R.; Kumar, S.; Kadu, A.; Patil, R. A Comprehensive Review of Monoclonal Antibodies in Modern Medicine: Tracing the Evolution of a Revolutionary Therapeutic Approach. Cureus 2024, 16, e61983. [Google Scholar] [CrossRef] [PubMed]
- Shimabukuro-Vornhagen, A.; Boll, B.; Schellongowski, P.; Valade, S.; Metaxa, V.; Azoulay, E.; von Bergwelt-Baildon, M. Critical care management of chimeric antigen receptor T-cell therapy recipients. CA Cancer J. Clin. 2022, 72, 78–93. [Google Scholar] [CrossRef] [PubMed]
- Li, L.; Gao, Y.; Srivastava, R.; Wang, W.; Xiong, Q.; Fang, Z.; Pelayo, A.; Denson, C.; Goswami, A.; Harari-Steinfeld, R.; et al. Lentiviral delivery of combinatorial CAR/CRISPRi circuit into human primary T cells is enhanced by TBK1/IKKvarepsilon complex inhibitor BX795. J. Transl. Med. 2020, 18, 363. [Google Scholar] [CrossRef] [PubMed]
- Luvai, A.; Mbagaya, W.; Hall, A.S.; Barth, J.H. Rosuvastatin: A review of the pharmacology and clinical effectiveness in cardiovascular disease. Clin. Med. Insights Cardiol. 2012, 6, 17–33. [Google Scholar] [CrossRef] [PubMed]
- Boyd, M.; Mairs, R.J.; Keith, W.N.; Ross, S.C.; Welsh, P.; Akabani, G.; Owens, J.; Vaidyanathan, G.; Carruthers, R.; Dorrens, J. An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects. J. Gene Med. 2004, 6, 937–947. [Google Scholar] [CrossRef] [PubMed]
- Shi, Z.; Hu, C.; Zheng, X.; Sun, C.; Li, Q. Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells. Exp. Hematol. Oncol. 2024, 13, 55. [Google Scholar] [CrossRef] [PubMed]
- Russell-Jones, G.; McTavish, K.; McEwan, J.; Rice, J.; Nowotnik, D. Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours. J. Inorg. Biochem. 2004, 98, 1625–1633. [Google Scholar] [CrossRef] [PubMed]
- Guo, W.; Deng, L.; Chen, Z.; Chen, Z.; Yu, J.; Liu, H.; Li, T.; Lin, T.; Chen, H.; Zhao, M.; et al. Vitamin B12-conjugated sericin micelles for targeting CD320-overexpressed gastric cancer and reversing drug resistance. Nanomedicine 2019, 14, 353–370. [Google Scholar] [CrossRef] [PubMed]
- Chen, Z.; Liang, Y.; Feng, X.; Liang, Y.; Shen, G.; Huang, H.; Chen, Z.; Yu, J.; Liu, H.; Lin, T.; et al. Vitamin-B12-conjugated PLGA-PEG nanoparticles incorporating miR-532-3p induce mitochondrial damage by targeting apoptosis repressor with caspase recruitment domain (ARC) on CD320-overexpressed gastric cancer. Mater. Sci. Eng. C 2021, 120, 111722. [Google Scholar] [CrossRef] [PubMed]
- Quadros, E.V.; Nakayama, Y.; Sequeira, J.M. Saporin conjugated monoclonal antibody to the transcobalamin receptor TCblR/CD320 is effective in targeting and destroying cancer cells. J. Cancer Ther. 2013, 4, 1074–1081. [Google Scholar] [CrossRef] [PubMed]
- Man, S.M.; Place, D.E.; Kuriakose, T.; Kanneganti, T.-D. Interferon-inducible guanylate-binding proteins at the interface of cell-autonomous immunity and inflammasome activation. J. Leukoc. Biol. 2017, 101, 143–150. [Google Scholar] [CrossRef] [PubMed]
- Nyabuto, G.O.; Wilson, J.P.; Heilman, S.A.; Kalb, R.C.; Kopacz, J.P.; Abnave, A.V.; Vestal, D.J. The Large GTPase, GBP-2, regulates Rho family GTPases to inhibit migration and invadosome formation in breast cancer cells. Cancers 2021, 13, 5632. [Google Scholar] [CrossRef] [PubMed]
- Xu, H.; Jin, J.; Chen, Y.; Wu, G.; Zhu, H.; Wang, Q.; Wang, J.; Li, S.; Grigore, F.-N.; Ma, J.; et al. GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair. Oncogene 2022, 41, 3876–3885. [Google Scholar] [CrossRef] [PubMed]
- Schnoor, M.; Betanzos, A.; Weber, D.A.; Parkos, C.A. Guanylate-binding protein-1 is expressed at tight junctions of intestinal epithelial cells in response to interferon-gamma and regulates barrier function through effects on apoptosis. Mucosal Immunol. 2009, 2, 33–42. [Google Scholar] [CrossRef] [PubMed]
- Birge, R.B.; Kalodimos, C.; Inagaki, F.; Tanaka, S. Crk and CrkL adaptor proteins: Networks for physiological and pathological signaling. Cell Commun. Signal. 2009, 7, 13. [Google Scholar] [CrossRef] [PubMed]
- Tsuda, M.; Tanaka, S. Roles for crk in cancer metastasis and invasion. Genes Cancer 2012, 3, 334–340. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Wang, F.; Qi, Y. MiR-126 inhibits the invasion of gastric cancer cell in part by targeting Crk. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 2031–2037. [Google Scholar] [PubMed]
- Yeo, M.G.; Sung, B.H.; Oh, H.J.; Park, Z.Y.; Marcantonio, E.E.; Song, W.K. Focal adhesion targeting of v-Crk is essential for FAK phosphorylation and cell migration in mouse embryo fibroblasts deficient src family kinases or p130CAS. J. Cell. Physiol. 2008, 214, 604–613. [Google Scholar] [CrossRef] [PubMed]
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